CN115671040B - External preparation for controlling animal parasite infection - Google Patents
External preparation for controlling animal parasite infection Download PDFInfo
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- CN115671040B CN115671040B CN202110824165.0A CN202110824165A CN115671040B CN 115671040 B CN115671040 B CN 115671040B CN 202110824165 A CN202110824165 A CN 202110824165A CN 115671040 B CN115671040 B CN 115671040B
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- external preparation
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- preparation
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- dipropylene glycol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 82
- 208000030852 Parasitic disease Diseases 0.000 title claims abstract description 19
- 244000000054 animal parasite Species 0.000 title claims abstract description 12
- 230000036281 parasite infection Effects 0.000 title claims abstract description 12
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 29
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 27
- 239000003120 macrolide antibiotic agent Substances 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims description 41
- QWOZZTWBWQMEPD-UHFFFAOYSA-N 1-(2-ethoxypropoxy)propan-2-ol Chemical compound CCOC(C)COCC(C)O QWOZZTWBWQMEPD-UHFFFAOYSA-N 0.000 claims description 36
- SLWWJZMPHJJOPH-PHDIDXHHSA-N 3-dehydroshikimic acid Chemical compound O[C@@H]1CC(C(O)=O)=CC(=O)[C@H]1O SLWWJZMPHJJOPH-PHDIDXHHSA-N 0.000 claims description 31
- SLWWJZMPHJJOPH-UHFFFAOYSA-N DHS Natural products OC1CC(C(O)=O)=CC(=O)C1O SLWWJZMPHJJOPH-UHFFFAOYSA-N 0.000 claims description 31
- -1 isoxazoline compound Chemical class 0.000 claims description 31
- 235000006708 antioxidants Nutrition 0.000 claims description 28
- AFJYYKSVHJGXSN-KAJWKRCWSA-N selamectin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1C(/C)=C/C[C@@H](O[C@]2(O[C@@H]([C@@H](C)CC2)C2CCCCC2)C2)C[C@@H]2OC(=O)[C@@H]([C@]23O)C=C(C)C(=N\O)/[C@H]3OC\C2=C/C=C/[C@@H]1C AFJYYKSVHJGXSN-KAJWKRCWSA-N 0.000 claims description 25
- 229960002245 selamectin Drugs 0.000 claims description 25
- 239000006184 cosolvent Substances 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
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- YZBLFMPOMVTDJY-CBYMMZEQSA-N moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)\C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-CBYMMZEQSA-N 0.000 claims description 12
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- JUUBCHWRXWPFFH-UHFFFAOYSA-N Hydroxytyrosol Chemical compound OCCC1=CC=C(O)C(O)=C1 JUUBCHWRXWPFFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- HGXBRUKMWQGOIE-AFHBHXEDSA-N (+)-pinoresinol Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@@H]3[C@@H]([C@H](OC3)C=3C=C(OC)C(O)=CC=3)CO2)=C1 HGXBRUKMWQGOIE-AFHBHXEDSA-N 0.000 claims description 2
- CUVLMZNMSPJDON-UHFFFAOYSA-N 1-(1-butoxypropan-2-yloxy)propan-2-ol Chemical compound CCCCOCC(C)OCC(C)O CUVLMZNMSPJDON-UHFFFAOYSA-N 0.000 claims description 2
- RWNUSVWFHDHRCJ-UHFFFAOYSA-N 1-butoxypropan-2-ol Chemical compound CCCCOCC(C)O RWNUSVWFHDHRCJ-UHFFFAOYSA-N 0.000 claims description 2
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- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 claims description 2
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- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 claims 1
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- 230000000749 insecticidal effect Effects 0.000 abstract description 6
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 abstract description 5
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- UNBDDZDKBWPHAX-UHFFFAOYSA-N n,n-di(propan-2-yl)formamide Chemical compound CC(C)N(C=O)C(C)C UNBDDZDKBWPHAX-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses an external preparation for controlling animal parasite infection, which is characterized by comprising isoxazoline, macrolide, acceptable liquid carrier medium and antioxidant. The composition has broad insecticidal activity, and the external preparation has no adverse reaction to skin and long-lasting stability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, relates to an external preparation of a veterinary antibacterial drug, and in particular relates to an external preparation for controlling animal parasite infection.
Technical Field
Controlling parasitic infections of animal groups has been an important global task. Pathogenic organisms can be classified as endoparasitic organisms of the nematoda, cestoda and trematoda or protozoan phylum, or ectoparasitic organisms of the arthropoda phylum. The former include infections of the stomach, intestinal tract, lymphatic system, tissues, liver, lung, heart and brain. The latter involves ectoparasites including ticks, mites, lice, flies and fleas, which often act as a vehicle and intermediate host for the transmission of endoparasites to animal hosts.
Although many ectoparasiticides and endoparasiticides are in use, these have a number of problems, such as limited spectrum of activity, the need for repeated treatments, and in many cases parasitically generated drug resistance.
The isoxazoline compound is a broad-spectrum pesticide, has good insecticidal activity on pests such as ticks, fleas, lice, hemiptera, diptera and the like, and has higher toxicity or equal toxicity to common pesticides. The macrolide compound is an antibiotic fermented by new recombinant strains, has wide inhibition and killing effects on parasites in the body and the outside of a plurality of animals, comprises fleas, scabies, ticks, hookworms, lice, nematodes, heartworms and the like, and has the advantages of good curative effect, low toxicity and the like.
The combination of the isoxazolines and the macrolides has obvious advantages in the aspect of insecticidal activity spectrum and has obvious inhibition effect on different parasites. The external preparation has basically consistent drug effect with the oral tablet, the external preparation is more convenient to use, has quick effect and obvious targeting effect, and the combined external preparation of the isoxazoline and the macrolide has obvious inhibiting and killing effects on most of internal parasites and external parasites, so that the isoxazoline and the macrolide are suitable for being prepared into external preparations for expelling parasites.
However, the existing external preparations on the market are added with a certain proportion of synthetic antioxidant butylhydroxytoluene to ensure the stability of the external solvent. Butylated Hydroxytoluene (BHT) is a common oil antioxidant used in external preparations to improve the stability of dosage forms. The cosmetic is used as a preservative, and the addition amount is generally small. The studies of a plurality of organizations such as world health organization, european style children protection organization, british biological industry association and the like show that the butylhydroxytoluene can be absorbed by skin, and can easily cause skin inflammation and allergy after long-term use or once excessive use, even can have adverse effects on liver, spleen and lung, and simultaneously the butylhydroxytoluene can change color and lose activity under the conditions of light, humidity, heat and the like, so that the antioxidant effect of the butylhydroxytoluene is obviously reduced.
The components of the pharmaceutical preparation have higher irritation to the body than the components of the cosmetic, the requirement on the stability of the pharmaceutical preparation is higher, the dosage of the stabilizer needs to be increased compared with the dosage of the stabilizer, and in order to avoid the side effect of the pharmaceutical preparation on the skin, and simultaneously, the stability of the properties and the efficacy of the pharmaceutical preparation is continuously maintained, so that the components of the external antibacterial pharmaceutical preparation are urgently needed to be improved.
Disclosure of Invention
Based on the problems existing in the practical application, the invention aims to provide an external preparation for controlling animal parasite infection. The composition has broad insecticidal activity, and the external preparation has no adverse reaction to skin and long-lasting stability.
In order to achieve the above purpose, the technical scheme of the invention is as follows: an external preparation containing an isoxazoline and macrolide pharmaceutical composition is provided, which comprises an isoxazoline compound, a macrolide compound, an acceptable liquid carrier vehicle and an antioxidant.
An external preparation for controlling parasitic infection in animals, wherein the external preparation comprises isoxazolines, acceptable liquid carrier vehicles and antioxidants.
Preferably, the antioxidant is 3-dehydroshikimic acid.
More preferably, the antioxidant may be 3-dehydroshikimic acid or a combination of 3-dehydroshikimic acid with one or more of 2-phenyl chromanone, vitamin E, beta-carotene, ascorbic acid, inositol phosphate, hydroxytyrosol, pinoresinol, catechins.
The isoxazoline compound in the external preparation is selected from one or more of fluorine Lei Lana, aforana, salolana and rotilana.
The liquid carrier medium is a solvent and a cosolvent, wherein the solvent is one or more of dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, dipropylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether and propylene glycol monobutyl ether. The cosolvent is selected from one or more of dimethylformamide, N-dimethylacetamide, dimethylformamide, diethylformamide, dimethyl sulfoxide, diisopropylformamide, acetone, ethanol and isopropanol.
The external preparation is a compound of multiple types of medicines, can be combined with a macrolide compound to expand the broad spectrum of antibacterial activity, and the macrolide compound can be selected from one or more of ivermectin, moxidectin, milbemycin, selamectin, emamectin, raltegraxin or lepidomycin.
The external preparation contains 10-200 mg/ml of isoxazoline compound and 10-60 mg/ml of macrolide compound according to the mass ratio of the external preparation to the total volume (w/v).
Preferably, the external preparation contains 50-160 mg/ml of isoxazoline compound and 20-50 mg/ml of macrolide compound according to the mass ratio of the external preparation to the total volume (w/v) of the external preparation.
More preferably, the external preparation also comprises 0.5-2.0 mg/ml of 3-dehydroshikimic acid according to the mass to total volume ratio of the external preparation; the dosage of the solvent is 85-95% of the total volume of the preparation solution, and the dosage of the cosolvent is 5-15% of the total volume of the preparation solution.
The invention relates to a preparation method of an external preparation for controlling animal parasite infection, which comprises the following specific steps: adding cosolvent into isoxazoline compound, macrolide compound and antioxidant, adding solvent at 80%, controlling temperature at 30-40deg.C, clarifying, adding residual solvent, and packaging into low molecular weight polyethylene sealed tank.
The Butylhydroxytoluene (BHT) referred to in the present invention is also known as dibutylhydroxytoluene (But y lated H y dox y Toluene) is also known as 2, 6-di-tert-butyl-p-cresol, which is an antioxidant and antiseptic, and has the function of resisting oxidation of oil and fat, and excessive addition of the antioxidant is liable to cause skin inflammation and allergy. The cosmetic composition review board has demonstrated that BHT concentrations in cosmetics are typically less than 0.1% and that BHT, although absorbed by the skin, does not enter the blood stream and low concentrations of BHT are not susceptible to and risk of carcinogenesis.
The 3-dehydroshikimic acid (DHS) is an important intermediate in the biosynthetic metabolic pathway of aromatic amino acids in microorganisms and plants. The 3-dehydroshikimic acid is also a very effective antioxidant, the activity of which is superior to that of some commercial antioxidants such as gallic acid, propyl gallic acid, butyl hydroxy anisole, butyl hydroxy toluene and the like, and has important application value.
The cosolvent is also called a cosolvent, and is an auxiliary solvent capable of improving the solubility of the main solvent in the solution. Most of the cosolvents are organic solvents, but the dissolution capacity of the main solvent can be improved by adding a small amount. Is commonly used for preparing missible oil and oil agent to improve the concentration of the effective components of the missible oil and the oil agent. Especially, when preparing high-concentration emulsifiable concentrates and ultra-low volume oil solutions, a certain cosolvent is needed.
The external preparation for controlling animal parasite infection provided by the invention has the following advantages:
1. the combined solvent and the cosolvent are adopted to increase the dissolution of the solvent to the medicine, thereby being beneficial to improving the content of the effective substances of the preparation and the stability of the preparation.
2. The antioxidant such as 3-dehydroshikimic acid (DHS) is adopted, so that the irritation is small, side reactions and harm are not caused by increasing the dosage, the compatibility with component solvents and effective medicines is good, the oxidation resistance of the medicinal preparation is improved, and the continuous stability is facilitated.
3. The cosolvent with reducibility and the natural antioxidant are selected to improve the stability of the external preparation, and meanwhile, the transdermal experiments show that the external preparation has a transdermal promoting effect and obvious parasite inhibition and killing effects.
Drawings
FIG. 1 shows the plasma concentration versus time profile of Florarader using the product of example 1 of the present invention;
FIG. 2 shows the blood concentration versus time profile of selamectin after use of the product of example 1 of the present invention.
Detailed Description
The invention will be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions and corresponding modifications to the technical features of the present invention are included within the scope of the present invention.
The instruments, reagents, materials, etc. according to the present examples are conventional instruments, reagents, materials, etc. existing in the prior art, unless otherwise specified, and are commercially available, and the experimental methods, detection methods, etc. according to the following examples are conventional experimental methods, detection methods, etc. existing in the prior art, unless otherwise specified.
EXAMPLES 1-5 preparation of compositions for external preparation for controlling parasitic infection in animals according to different compositions of the method of the present application
Example 1
Active ingredients: fluorine Lei Lana mg, selamectin 300mg
Solvent: dipropylene glycol monoethyl ether 8.5ml
Cosolvent: n, N-dimethylacetamide 1.5ml
Antioxidant: 10mg of 3-dehydroshikimic acid
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana, selamectin and 3-dehydroshikimic acid, adding 1.5ml of N, N-dimethylacetamide, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, adding the rest solvent after clarification, and filling into a low molecular weight polyethylene sealing tank to obtain the product.
Example 2
Active ingredients: fluorine Lei Lana mg, selamectin 240mg
Solvent: dipropylene glycol monoethyl ether 9ml
Cosolvent: n, N-dimethylacetamide 1ml
Antioxidant: 8mg of 3-dehydroshikimic acid
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana, selamectin and 3-dehydroshikimic acid, adding 1ml of N, N-dimethylacetamide, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the rest solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the final product.
Example 3
Active ingredients: fluorine Lei Lana mg, selamectin 360mg
Solvent: dipropylene glycol monoethyl ether 9.5ml
Cosolvent: n, N-dimethylacetamide 0.5ml
Antioxidant: 12mg of 3-dehydroshikimic acid
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana, selamectin and 3-dehydroshikimic acid, adding 1ml of N, N-dimethylacetamide, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the rest solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the final product.
Example 4
Active ingredients: sha Luola Na 100mg, sorangin 300mg
Solvent: dipropylene glycol monoethyl ether 9ml
Cosolvent: n, N-dimethylacetamide 1ml
Antioxidant: 10mg of 3-dehydroshikimic acid
The preparation method comprises the following steps: taking sallow, selamectin and 3-dehydroshikimic acid with the prescription amount, adding 1ml of N, N-dimethylacetamide, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, adding the residual solvent after clarification, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
Example 5
Active ingredients: fluorine Lei Lana mg and moxidectin 100mg
Solvent: dipropylene glycol monoethyl ether 9ml
Cosolvent: n, N-dimethylacetamide 1ml
Antioxidant: 10mg of 3-dehydroshikimic acid
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana, moxidectin and 3-dehydroshikimic acid, adding 1ml of N, N-dimethylacetamide, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the residual solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
EXAMPLE 6 preparation of different compositions of external preparation for controlling parasitic infection in animals
Comparative example 1
Active ingredients: fluorine Lei Lana mg, selamectin 300mg
Solvent: dipropylene glycol monoethyl ether 10ml
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana and selamectin, adding 80% of dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, adding the rest solvent after clarification, and filling into a low molecular weight polyethylene sealed tank to obtain the compound.
Comparative example 2
Active ingredients: fluorine Lei Lana mg, selamectin 300mg
Solvent: dipropylene glycol monoethyl ether 10ml
Antioxidant: butylene 1mg
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana, selacin and butylhydroxytoluene, adding 80% of dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, and filling the mixture into a low molecular weight polyethylene sealing tube to obtain the finished product.
Comparative example 3
Active ingredients: fluorine Lei Lana mg, selamectin 300mg
Solvent: dipropylene glycol monoethyl ether 8.5ml
Cosolvent: n, N-dimethylacetamide 1.5ml
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana and selamectin, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, adding 1.5ml of N, N-dimethylacetamide, clarifying, adding the residual solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the compound.
Comparative example 4
Active ingredients: fluorine Lei Lana mg, selamectin 300mg
Solvent: dipropylene glycol monoethyl ether 10ml
Antioxidant: 10mg of 3-dehydroshikimic acid
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana, selamectin and 3-dehydroshikimic acid, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, adding the residual solvent after clarification, and filling into a low molecular weight polyethylene sealing tank to obtain the product.
Comparative example 5
Active ingredients: sha Luola Na 100mg, sorangin 300mg
Solvent: dipropylene glycol monoethyl ether 300ml
The preparation method comprises the following steps: taking sallow and selacin with prescription amount, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the residual solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
Comparative example 6
Active ingredients: sha Luola Na 100mg, sorangin 300mg
Solvent: dipropylene glycol monoethyl ether 10ml
Antioxidant: butylene 1mg
The preparation method comprises the following steps: taking sallow, selacin and butylhydroxytoluene with the prescription amount, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the residual solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
Comparative example 7
Active ingredients: sha Luola Na 100mg, sorangin 300mg
Solvent: dipropylene glycol monoethyl ether 9ml
Cosolvent: n, N-dimethylacetamide 1ml
The preparation method comprises the following steps: taking sallow and selacin with prescription amount, adding 1ml of N, N-dimethylacetamide, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, adding the residual solvent after clarification, and filling into a low molecular weight polyethylene sealed tank to obtain the sallow and selacin.
Comparative example 8
Active ingredients: sha Luola Na 100mg, sorangin 300mg
Solvent: dipropylene glycol monoethyl ether 10ml
Antioxidant: 10mg of 3-dehydroshikimic acid
The preparation method comprises the following steps: taking sallow, selamectin and 3-dehydroshikimic acid with the prescription amount, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the residual solvent, and filling into a low molecular weight polyethylene sealing tank.
Comparative example 9
Active ingredients: fluorine Lei Lana mg and moxidectin 100mg
Solvent: dipropylene glycol monoethyl ether 10ml
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana and moxidectin, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the rest solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
Comparative example 10
Active ingredients: fluorine Lei Lana mg and moxidectin 100mg
Solvent: dipropylene glycol monoethyl ether 10ml
Antioxidant: butylene oxide 8mg
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana, moxidectin and butylhydroxytoluene, adding 80% of dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the residual solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
Comparative example 11
Active ingredients: fluorine Lei Lana mg and moxidectin 100mg
Solvent: dipropylene glycol monoethyl ether 9ml
Cosolvent: n, N-dimethylacetamide 1ml
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana and moxidectin, adding 1ml of N, N-dimethylacetamide, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the rest solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
Comparative example 12
Active ingredients: fluorine Lei Lana mg and moxidectin 100mg
Solvent: dipropylene glycol monoethyl ether 10ml
Antioxidant: 16mg of 3-dehydroshikimic acid
The preparation method comprises the following steps: taking the prescription amount of fluorine Lei Lana, moxidectin and 3-dehydroshikimic acid, adding 80% dipropylene glycol monoethyl ether, controlling the temperature to be 30-40 ℃, clarifying, adding the residual solvent, and filling into a low molecular weight polyethylene sealed tank to obtain the product.
Example 7 stability test
The external preparation solutions of examples 1 to 5 and comparative examples 1 to 12 were placed in a constant temperature and humidity box at a temperature of 40.+ -. 2 ℃ and a relative humidity RH of 75%.+ -. 5%, and were sampled at the end of 3 months and 6 months, respectively, to examine the properties and contents thereof. The test results are shown in tables 1 to 3:
TABLE 1 test results of 3 month and 6 month accelerated topical solutions
TABLE 2 results of 3 month and 6 month test of topical solutions acceleration
TABLE 3 results of 3 month and 6 month test of topical solutions acceleration
As can be seen from tables 1 to 3, the external preparation of the invention has stable content through an acceleration experiment, and the HPLC purities of a plurality of isoxazolines and macrolide compounds are compared, so that the stability of the external preparation of the 3-dehydroshikimic acid and the reducing solvent is better than that of the butylhydroxytoluene, and the stability of the external preparation of the 3-dehydroshikimic acid compounded by the reducing solvent is optimal, and the HPLC purities of fluorine Lei Lana and selamectin are basically consistent under the condition of accelerating for 6 months.
The compound preparation of the isoxazoline and the macrolide with stable content can be obtained through the present prescription, and compared with other products on the market, the pesticide effect is better through the comparison of the efficacy experiment, and meanwhile, the use of artificial synthetic antioxidants is avoided, so that the compound preparation is suitable for future commercial production.
Example 8 test for evaluating efficacy of Compound external drops against insect repellent
(1) In vitro insect repellent (tick)
In this evaluation, beagle dogs of mixed sex were used and assigned to the blank, commercially available positive and inventive examples 1 to 3 groups, and the experimental dogs were challenged with 50 adult ticks that were not fed (red-fan head ticks).
Dogs received treatment on day 0 at a dose of 40mg/kg b.w. fluorine Lei Lana and 6mg/kg b.w. selamectin. The formulation was administered using a pipette. The dose is administered in the form of a line at the back neck of the skull base.
Average rates of detection of ticks in dogs at day 0, day 5, day 10, day 20 and day 30 after dosing were counted for each group of drugs, and any immediate response of dogs to treatment was observed at day 1, day 2 and day 7 after dosing, as well as adverse effects, skin irritation and the characteristics of the test formulations after treatment.
Table 4 average rate of drug detection of tick in dogs
(2) Insect repellent in vivo
In this evaluation, beagle dogs of mixed sex were used and assigned to a blank control group, a commercially available positive group and a test group, and the test dogs were found to be infected with a large number of intestinal parasites (including hookworms, whipworms, roundworms, tapeworms, etc.) by a laboratory fecal floatation method and a direct smear method.
Dogs received treatment on day 0 at a dose of 40mg/kg b.w. fluorine Lei Lana and 6mg/kg b.w. selamectin. The formulation was administered using a pipette. The dose is administered in the form of a line at the back neck of the skull base.
Average detection rates of nematodes and tapeworms in dogs were counted for each group of drugs on days 0, 5, 10, 20 and 30 after administration, and any immediate response of dogs to treatment was observed on days 1, 2 and 7 after administration, and adverse reactions, skin irritation and properties of the test preparations after treatment were observed.
Table 5 drug detection rate of canine endoparasites
The table shows that the invention has obvious insecticidal effect on the internal and external parasites of dogs, the detection rate is lower than that of a blank control group and a commercial positive group, the action time is long, and the invention has good in-vitro and in-vivo insecticidal effect in 30 days. The test result shows that the long-acting external liquid preparation for controlling animal parasite infection prepared by the embodiment of the invention has good parasite-expelling effect on the internal and external parasites of dogs within 30 days.
Example 9 blood concentration test
A single transdermal administration of a compound formulation based on fluorine Lei Lana, selamectin, fluo Lei Lana (40 mg/kg b.w.), selamectin (6 mg/kg b.w.), was performed to dogs, and the dogs were observed for local and systemic tolerability of the treatment and the cosmetic appearance of the site of administration was evaluated. Plasma samples were collected from all dogs on day 0, day 1, day 3, day 5, day 7 and weekly thereafter until day 35, 2 hours, 4 hours, 8 hours before and after dosing. Plasma was analyzed for fluorine Lei Lana and selamectin concentrations.
Results: the mean plasma concentrations of fluorine Lei Lana and selamectin in dogs are shown in fig. 1 and 2, and no local or systemic adverse effects were observed. The cosmetic appearance is acceptable.
Example 10 safety test
About 20g of Kunming mice were selected and randomly divided into 4 groups of 10 male and female halves. Group 1 is control group, intramuscular injection of 0.5m1 physiological saline; groups 2-4 are test groups, the long-acting compound insect repellent liquid preparation of the embodiment of the invention with different dosages (high dosage, medium dosage and low dosage) is selected for preparation, 5.0mL, 3.0mL and 1.0mL are intramuscular injected for 1 time, and then continuous observation is carried out for 3-5 months, feeding, drinking, behavior change and death conditions of mice are recorded, 3 mice are randomly selected for dissection after the test, pathological changes of organs are observed, and the record is carried out.
Results: the mice in the control group and the mice in the test 2-4 groups are not dead during the test, have normal feeding and drinking, have no obvious abnormality in behaviors, and have no abnormal lesions in the heart, liver, spleen, lung, kidney, stomach and intestinal tracts through the section examination, and have no obvious difference from the control group. The result shows that the long-acting external liquid preparation for controlling animal parasite infection prepared by the invention is safe to use.
Claims (6)
1. An external preparation for controlling parasitic infection in animals, which comprises a drug efficacy component, a liquid carrier medium and an antioxidant containing 3-dehydroshikimic acid, wherein the drug efficacy component is an isoxazoline compound and a macrolide compound; the isoxazoline compound is fluororalrana or salrana; the macrolide compound is selamectin or moxidectin; the liquid carrier vehicle comprises a solvent and a cosolvent, wherein the cosolvent is N, N-dimethylacetamide, and the solvent is one or a mixture of more of dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether, dipropylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether and propylene glycol monobutyl ether.
2. An external preparation for controlling parasitic infection in animals according to claim 1, wherein the antioxidant is 3-dehydroshikimic acid or a combination of 3-dehydroshikimic acid and one or more of 2-phenyl chromone, vitamin E, beta-carotene, ascorbic acid, inositol phosphate, hydroxytyrosol, pinoresinol, catechin.
3. The external preparation for controlling animal parasite infection according to claim 1, wherein the external preparation contains 10-200 mg/ml of isoxazoline compound and 10-60 mg/ml of macrolide compound based on the total volume ratio of mass to external preparation.
4. An external preparation for controlling animal parasite infection according to claim 3, wherein the external preparation contains 50-160 mg/ml of isoxazoline compound and 20-50 mg/ml of macrolide compound based on the total volume ratio of mass to external preparation.
5. The external preparation for controlling parasitic infection in animals according to claim 4, wherein the external preparation comprises 0.5-2.0 mg/ml of 3-dehydroshikimic acid based on the total volume ratio of the external preparation; the dosage of the solvent is 85-95% of the total volume of the preparation solution, and the dosage of the cosolvent is 5-15% of the total volume of the preparation solution.
6. The method for preparing an external preparation for controlling animal parasite infection according to any one of claims 1 to 5, comprising the following specific steps: adding cosolvent into the isoxazoline compound, macrolide compound and antioxidant in the prescribed amount, adding 80% of the total solvent, controlling the temperature to be 30-40 ℃, clarifying, adding the rest solvent, and filling into a low molecular weight polyethylene sealing tank.
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| US6426333B1 (en) * | 1996-09-19 | 2002-07-30 | Merial | Spot-on formulations for combating parasites |
| AU2016210773A1 (en) * | 2015-02-21 | 2016-09-29 | Othman Abdul Rahim Radi Al Hanbali | An anti-parasitic formulation and a method for treating parasitic infestations in an animal |
| CN110167540A (en) * | 2016-10-31 | 2019-08-23 | 斯克利普斯研究所 | For preventing the method and composition of the propagation of vector-borne disease |
| CN113038937A (en) * | 2018-09-05 | 2021-06-25 | 硕腾服务有限责任公司 | Palatable antiparasitic formulations |
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2021
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6426333B1 (en) * | 1996-09-19 | 2002-07-30 | Merial | Spot-on formulations for combating parasites |
| AU2016210773A1 (en) * | 2015-02-21 | 2016-09-29 | Othman Abdul Rahim Radi Al Hanbali | An anti-parasitic formulation and a method for treating parasitic infestations in an animal |
| CN110167540A (en) * | 2016-10-31 | 2019-08-23 | 斯克利普斯研究所 | For preventing the method and composition of the propagation of vector-borne disease |
| CN113038937A (en) * | 2018-09-05 | 2021-06-25 | 硕腾服务有限责任公司 | Palatable antiparasitic formulations |
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